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Mutation of NIMA-related kinase 1 (NEK1) leads to chromosome instability

  • Author(s): Chen, Yumay
  • Chen, Chi-Fen
  • Chiang, Huai-Chin
  • Pena, Michelle
  • Polci, Rosaria
  • Wei, Randy L
  • Edwards, Robert A
  • Hansel, Donna E
  • Chen, Phang-Lang
  • Riley, Daniel J
  • et al.
Abstract

Background: NEK1, the first mammalian ortholog of the fungal protein kinase never-in-mitosis A (NIMA), is involved early in the DNA damage sensing/repair pathway. A defect in DNA repair in NEK1-deficient cells is suggested by persistence of DNA double strand breaks after low dose ionizing radiation (IR). NEK1-deficient cells also fail to activate the checkpoint kinases CHK1 and CHK2, and fail to arrest properly at G1/S or G2/M-phase checkpoints after DNA damage. Results: We show here that NEK1-deficient cells suffer major errors in mitotic chromosome segregation and cytokinesis, and become aneuploid. These NEK1-deficient cells transform, acquire the ability to grow in anchorageindependent conditions, and form tumors when injected into syngeneic mice. Genomic instability is also manifest in NEK1 +/- mice, which late in life develop lymphomas with a much higher incidence than wild type littermates. Conclusion: NEK1 is required for the maintenance of genome stability by acting at multiple junctures, including control of chromosome stability.

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